tbuckley/cabot-search huggingface dataset:
Durable response of lung carcinoma patients to EGFR tyrosine kinase inhibitors is determined by germline polymorphisms in some immune-related genes
Authors: Lorraine Dalens, Julie Niogret, Corentin Richard, Sandy Chevrier, Pascal Foucher, Bruno Coudert, Aurélie Lagrange, Laure Favier, Virginie Westeel, Stefano Kim, Olivier Adotevi, Caroline Chapusot, Laurent Martin, Laurent Arnould, Courèche-Guillaume Kaderbhai, Romain Boidot
Journal: Molecular Cancer (2023)

Abstract Background Non-small cell lung cancer is a very poor prognosis disease. Molecular analyses have highlighted several genetic alterations which may be targeted by specific therapies. In clinical practice, progression-free survival on EGFR TKI treatment is between 12 and 14 months. However, some patients progress rapidly in less than 6 months, while others remain free of progression for 16 months or even longer during EGFR TKI treatment. Methods We sequenced tumor exomes from 135 lung cancer patients (79 with EGFR -wildtype (WT), 56 with EGFR -mutant tumors) enrolled in the ALCAPONE trial (genomic analysis of lung cancers by next generation sequencing for personalized treatment). Results Some germline polymorphisms were enriched in the EGFR -mutant subset compared to EGFR -WT tumors or to a reference population. However, the most interesting observation was the negative impact of some germline SNPs in immunity-related genes on survival on EGFR TKI treatment. Indeed, the presence of one of three particular SNPs in the HLA-DRB5 gene was associated with a decreased PFS on EGFR TKI . Moreover, some SNPs in the KIR3DL1 and KIR3DL2 genes were linked to a decrease in both progression-free and overall survival of patients with EGFR -mutant tumors. Conclusion Our data suggest that SNPs in genes expressed by immune cells may influence the response to targeted treatments, such as EGFR TKIs. This indicates that the impact of these cells may not be limited to modulating the response to immunotherapies. Further studies are needed to determine the exact mechanisms underlying this influence and to identify the associated predictive and prognostic markers that would allow to refine treatments and so improve lung cancer patient outcomes. Trial registration NCT02281214: NGS Genome Analysis in Personalization of Lung Cancer Treatment (ALCAPONE).
Optimizing detection of Alzheimer’s disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO
Authors: Zahinoor Ismail, Rebeca Leon, Byron Creese, Clive Ballard, Philippe Robert, Eric E. Smith
Journal: Molecular Neurodegeneration (2023)

Disease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally.
Nitric Oxide‐Assisted Photodynamic Therapy for Enhanced Penetration and Hypoxic Bacterial Biofilm Elimination
Authors: Xinyi Lv, Jingai Jiang, Jie Ren, Hui Li, Dongliang Yang, Xuejiao Song, Yanling Hu, Wenjun Wang, Xiaochen Dong
Journal: Advanced Healthcare Materials (2023)

The presence of a biofilm matrix barrier and hypoxic microenvironment within the biofilm significantly impedes the efficacy of photodynamic therapy for bacterial biofilm infections. Herein, a phototherapeutic nanoagent with type-I photodynamic behavior and nitric oxide (NO) release performance is reported for overcoming biofilm-associated infectious diseases. Sodium nitroprusside (SNP), a NO donor, is loaded onto amino-modified mesoporous silica nanoparticles (MSN) to form MSN@SNP NPs. The resulting nanoparticles are further modified with a porphyrin-based metal-organic framework (Ti-TCPP MOF) to obtain MSN@MOF/SNP NPs (MMS NPs) for phototherapeutic applications. In the hypoxia biofilm microenvironment, the MMS NPs release NO to enhance the biofilm permeability and induce the generation of hydroxyl radical (•OH) and superoxide anion radical (O2•- ) via Type-I photodynamic pathway under laser irradiation. Subsequently, the biofilm-associated infections are effectively eliminated through reactive oxygen species (ROS) and NO gas synergistic therapy. In addition, NO also stimulates collagen deposition and promotes angiogenesis in vivo. Therefore, the MMS NPs efficiently treat biofilm-related infections, providing an alternative approach to combat biofilm-associated infectious diseases.
A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors
Authors: Youchao Deng, Xiaosheng Song, Iredia D. Iyamu, Aiping Dong, Jinrong Min, Rong Huang
Journal: Acta Pharmaceutica Sinica B (2023)

Protein arginine methyltransferases (PRMTs) are attractive targets for developing therapeutic agents, but selective PRMT inhibitors targeting the cofactor SAM binding site are limited. Herein, we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea, potently and selectively inhibiting PRMT3/4/5. Importantly, crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4, providing a structural basis for the selectivity. In addition, YD1113 can be modified by introducing a substrate mimic to form a "T-shaped" bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets, exhibiting potent and selective inhibition to type I PRMTs (IC50 < 5 nmol/L). In summary, we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.
Pathophysiological roles and applications of glycosphingolipids in the diagnosis and treatment of cancer diseases
Authors: Xuefeng Jin, Guang-Yu Yang
Journal: Progress in Lipid Research (2023)

Glycosphingolipids (GSLs) are major amphiphilic glycolipids present on the surface of living cell membranes. They have important biological functions, including maintaining plasma membrane stability, regulating signal transduction, and mediating cell recognition and adhesion. Specific GSLs and related enzymes are abnormally expressed in many cancer diseases and affect the malignant characteristics of tumors. The regulatory roles of GSLs in signaling pathways suggest that they are involved in tumor pathogenesis. GSLs have therefore been widely studied as diagnostic markers of cancer diseases and important targets of immunotherapy. This review describes the tumor-related biological functions of GSLs and systematically introduces recent progress in using diverse GSLs and related enzymes to diagnose and treat tumor diseases. Development of drugs and biomarkers for personalized cancer therapy based on GSL structure is also discussed. These advances, combined with recent progress in the preparation of GSLs derivatives through synthetic biology technologies, suggest a strong future for the use of customized GSL libraries in treating human diseases.
Advanced nano-based strategies for mRNA tumor vaccine
Authors: Yangqi Qu, Jingjing Xu, Tong Zhang, Qinjun Chen, Tao Sun, Chen Jiang
Journal: Acta Pharmaceutica Sinica B (2023)

Tumor vaccine is a promising strategy for cancer immunotherapy by introducing tumor antigens into the body to activate specific anti-tumor immune responses. Along with the technological breakthroughs in genetic engineering and delivery systems, messenger ribonucleic acid (mRNA) technology has achieved unprecedented development and application over the last few years, especially the emergency use authorizations of two mRNA vaccines during the COVID-19 pandemic, which has saved countless lives and makes the world witness the powerful efficacy of mRNA technology in vaccines. However, unlike infectious disease vaccines, which mainly induce humoral immunity, tumor vaccines also need to activate potent cellular immunity to control tumor growth, which creates a higher demand for mRNA delivery to the lymphatic organs and antigen-presenting cells (APCs). Here we review the existing bottlenecks of mRNA tumor vaccines and advanced nano-based strategies to overcome those challenges, as well as future considerations of mRNA tumor vaccines and their delivery systems.
Predictors of laboratory-confirmed mpox in people with mpox-like illness
Authors: Isaac Núñez, Santa E. Ceballos-Liceaga, Alethse de la Torre, Gabriel García-Rodríguez, Irma López-Martínez, Juan Sierra-Madero, Juan L. Mosqueda-Gómez, Sergio Iván Valdés-Ferrer
Journal: Clinical Microbiology and Infection (2023)
First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection
Authors: Edward J. Gane, Won Kim, Tien Huey Lim, Pisit Tangkijvanich, Jung-Hwan Yoon, William Sievert, Wattana Sukeepaisarnjaroen, Alexander J. Thompson, Vedran Pavlovic, Bernadette Surujbally, Cynthia Wat, Bob D. Brown, Hardean E. Achneck, Man-Fung Yuen
Journal: Journal of Hepatology (2023)
Delirium assessment tools among hospitalized older adults: A systematic review and metaanalysis of diagnostic accuracy
Authors: Chia-Jou Lin, I.-Chang Su, Sheng-Wen Huang, Pin-Yuan Chen, Victoria Traynor, Hui-Chen (Rita) Chang, I.-Hsing Liu, Yun-Shuan Lai, Hsin-Chien Lee, Kaye Rolls, Hsiao-Yean Chiu
Journal: Ageing Research Reviews (2023)
Skin mesenchymal niches maintain and protect AML-initiating stem cells
Authors: Lakshmi Sandhow, Huan Cai, Elory Leonard, Pingnan Xiao, Luana Tomaipitinca, Alma Månsson, Makoto Kondo, Xiaoyan Sun, Anne-Sofie Johansson, Karl Tryggvason, Maria Kasper, Marcus Järås, Hong Qian
Journal: The Journal of Experimental Medicine (2023)

Leukemia cutis or leukemic cell infiltration in skin is one of the common extramedullary manifestations of acute myeloid leukemia (AML) and signifies a poorer prognosis. However, its pathogenesis and maintenance remain understudied. Here, we report massive AML cell infiltration in the skin in a transplantation-induced MLL-AF9 AML mouse model. These AML cells could regenerate AML after transplantation. Prospective niche characterization revealed that skin harbored mesenchymal progenitor cells (MPCs) with a similar phenotype as BM mesenchymal stem cells. These skin MPCs protected AML-initiating stem cells (LSCs) from chemotherapy in vitro partially via mitochondrial transfer. Furthermore, Lama4 deletion in skin MPCs promoted AML LSC proliferation and chemoresistance. Importantly, more chemoresistant AML LSCs appeared to be retained in Lama4−/− mouse skin after cytarabine treatment. Our study reveals the characteristics and previously unrecognized roles of skin mesenchymal niches in maintaining and protecting AML LSCs during chemotherapy, meriting future exploration of their impact on AML relapse.
Type I interferons drive MAIT cell functions against bacterial pneumonia
Authors: Juan Carlos López-Rodríguez, Steven J. Hancock, Kelin Li, Stefania Crotta, Christopher Barrington, Alejandro Suárez-Bonnet, Simon L. Priestnall, Jeffrey Aubé, Andreas Wack, Paul Klenerman, Jose A. Bengoechea, Patricia Barral
Journal: The Journal of Experimental Medicine (2023)

Mucosal-associated invariant T (MAIT) cells are abundant in the lung and contribute to host defense against infections. During bacterial infections, MAIT cell activation has been proposed to require T cell receptor (TCR)–mediated recognition of antigens derived from the riboflavin synthesis pathway presented by the antigen-presenting molecule MR1. MAIT cells can also be activated by cytokines in an MR1-independent manner, yet the contribution of MR1-dependent vs. -independent signals to MAIT cell functions in vivo remains unclear. Here, we use Klebsiella pneumoniae as a model of bacterial pneumonia and demonstrate that MAIT cell activation is independent of MR1 and primarily driven by type I interferons (IFNs). During Klebsiella infection, type I IFNs stimulate activation of murine and human MAIT cells, induce a Th1/cytotoxic transcriptional program, and modulate MAIT cell location within the lungs. Consequently, adoptive transfer or boosting of pulmonary MAIT cells protect mice from Klebsiella infection, with protection being dependent on direct type I IFN signaling on MAIT cells. These findings reveal type I IFNs as new molecular targets to manipulate MAIT cell functions during bacterial infections.
Thymic mimicry: The art of imitation
Authors: Vanja Cabric, Chrysothemis C. Brown
Journal: The Journal of Experimental Medicine (2023)

Display of tissue self-antigens within the thymus is critical for the regulation of self-reactive T cells. In this issue of JEM, Michelson et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20230461) continue to advance our understanding of self-antigen representation by medullary thymic epithelial cells, identifying a new role for Hnf4γ in the regulation of thymic mimetic cells as well as their peripheral counterparts.
miR-15/16 clusters restrict effector Treg cell differentiation and function
Authors: Jiayi Dong, William J. Huth, Nimi Marcel, Ziyue Zhang, Ling-Li Lin, Li-Fan Lu
Journal: The Journal of Experimental Medicine (2023)

Effector regulatory T cells (eTregs) exhibit distinct homeostatic properties and superior suppressor capacities pivotal for controlling immune responses mediated by their conventional T cell counterpart. While the role of microRNAs (miRNAs) in Tregs has been well-established, how miRNAs regulate eTregs remains poorly understood. Here, we demonstrate that miR-15/16 clusters act as key regulators in limiting eTreg responses. Loss of miR-15/16 clusters leads to increased eTreg frequencies with enhanced suppressor function. Consequently, mice with Treg-specific ablation of miR-15/16 clusters display attenuated immune responses during neuroinflammation and upon both infectious and non-infectious challenges. Mechanistically, miR-15/16 clusters exert their regulatory effect in part through repressing IRF4, a transcription factor essential for eTreg differentiation and function. Moreover, miR-15/16 clusters also directly target neuritin, an IRF4-dependent molecule, known for its role in Treg-mediated regulation of plasma cell responses. Together, we identify an miRNA family that controls an important Treg subset and further demonstrate that eTreg responses are tightly regulated at both transcriptional and posttranscriptional levels.
Immediate and sustained increases in the activity of vagal preganglionic neurons during exercise and after exercise training
Authors: Alla Korsak, Daniel O Kellett, Qadeer Aziz, Cali Anderson, Alicia D’Souza, Andrew Tinker, Gareth L Ackland, Alexander V Gourine
Journal: Cardiovascular Research (2023)

The brain controls the heart by dynamic recruitment and withdrawal of cardiac parasympathetic (vagal) and sympathetic activity. Autonomic control is essential for the development of cardiovascular responses during exercise, however, the patterns of changes in the activity of the two autonomic limbs, and their functional interactions in orchestrating physiological responses during exercise, are not fully understood. The aim of this study was to characterize changes in vagal parasympathetic drive in response to exercise and exercise training by directly recording the electrical activity of vagal preganglionic neurons in experimental animals (rats).
Donor circadian clock influences the long-term survival of heart transplantation by immunoregulation
Authors: Wai Yen Yim, Tixiusi Xiong, Bingchuan Geng, Li Xu, Yu Feng, Jiangyang Chi, Ruikang Guo, Chenghao Li, Yuqi Chen, Jiawei Shi, Yixuan Wang, Nianguo Dong
Journal: Cardiovascular Research (2023)

Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at different timing on survival after transplantation to explore novel criteria for donor selection.In primate heart, phase set enrichment analysis (PSEA) showed rhythmic transcripts were enriched in antigen processing and presentation during activation of circadian rhythm. Digital sorting of immune cell composition and single-sample gene set enrichment analysis (ssGSEA) in unused donor transcriptomes showed the pathway, positive regulation of circadian rhythm significantly correlates with allograft rejection and antigen presentation pathways as well as with increased compositions of matured dendritic cell, CD4+ T cell, and naive B cell. Single-centre retrospective cohort of 390 adult heart transplants between 1 January 2015 and 31 December 2020 was used to generate a propensity score matching (PSM) cohort. Survival curve differed significantly showing inferior long-term survival when donor hearts were procured at activation group (12 pm to 12 am) compared to repression group (12 am to 12 pm) (6-year survival: 64.2% vs. 75.8%, P = 0.0065). Activation group was also associated with significantly higher rates of in-hospital death, cardiopulmonary resuscitation, and usage of mechanical circulatory support after heart transplantation compared to repression group. Furthermore, tendency for post-transplant free of rejection rates was higher in repression group compared to activation group (acute rejection, Gehan-Breslow P = 0.11 and 0.04; chronic rejection, Log rank P = 0.077 and 0.15, in full and PSM cohorts, respectively). Adjusted Cox regression analysis showed that activation group was associated with 2.20 times increased hazard of death (hazard ratio: 2.20; 95% confidence interval: 1.23-3.95; P = 0.008) compared to repression group.Circadian immunity may represent donor-related risk factors for cardiac allograft rejection through activating genes related to antigen presentation pathway and immune cells oscillation at specific time of day. Molecular circadian clock should be considered during retrieval of cardiac allografts in order to maximize graft durability.
LncRNA-encoded peptides: unveiling their significance in cardiovascular physiology and pathology—current research insights
Authors: Li Zhang, Mi Tang, Haoyang Diao, Liling Xiong, Xiao Yang, Shasha Xing
Journal: Cardiovascular Research (2023)

Long non-coding RNAs (lncRNAs), which are RNA transcripts exceeding 200 nucleotides were believed to lack any protein-coding capacity. But advancements in -omics technology have revealed that some lncRNAs have small open reading frames (sORFs) that can be translated by ribosomes to encode peptides, some of which have important biological functions. These encoded peptides subserve important biological functions by interacting with their targets to modulate transcriptional or signalling axes, thereby enhancing or suppressing cardiovascular disease (CVD) occurrence and progression. In this review, we summarize what is known about the research strategy of lncRNA-encoded peptides, mainly comprising predictive websites/tools and experimental methods that have been widely used for prediction, identification, and validation. More importantly, we have compiled a list of lncRNA- encoded peptides, with a focus on those that play significant roles in cardiovascular physiology and pathology, including ENSRNOT (RNO)-sORF6/RNO-sORF7/RNO-sORF8, dwarf open reading frame (DOWRF), myoregulin (NLN), etc. Additionally, we have outlined the functions and mechanisms of these peptides in cardiovascular physiology and pathology, such as cardiomyocyte hypertrophy, myocardial contraction, myocardial infarction, and vascular remodelling. Finally, an overview of the existing challenges and potential future developments in the realm of lncRNA-encoded peptides was provided, with consideration given to prospective avenues for further research. Given that many lncRNA-encoded peptides have not been functionally annotated yet, their application in CVD diagnosis and treatment still requires further research.
Liver biopsy-based validation, confirmation and comparison of the diagnostic performance of established and novel non-invasive steatotic liver disease indexes: Results from a large multi-center study
Authors: Matina Kouvari, Laura Valenzuela-Vallejo, Valentina Guatibonza-Garcia, Stergios A. Polyzos, Yixiang Deng, Michail Kokkorakis, Melih Agraz, Sophia C. Mylonakis, Angeliki Katsarou, Ornella Verrastro, Georgios Markakis, Mohammed Eslam, Georgios Papatheodoridis, Jacob George, Geltrude Mingrone, Christos S. Mantzoros
Journal: Metabolism (2023)
Age of onset and cumulative risk of mental disorders: a cross-national analysis of population surveys from 29 countries
Authors: John J McGrath, Ali Al-Hamzawi, Jordi Alonso, Yasmin Altwaijri, Laura H Andrade, Evelyn J Bromet, Ronny Bruffaerts, José Miguel Caldas de Almeida, Stephanie Chardoul, Wai Tat Chiu, Louisa Degenhardt, Olga V Demler, Finola Ferry, Oye Gureje, Josep Maria Haro, Elie G Karam, Georges Karam, Salma M Khaled, Viviane Kovess-Masfety, Marta Magno, Maria Elena Medina-Mora, Jacek Moskalewicz, Fernando Navarro-Mateu, Daisuke Nishi, Oleguer Plana-Ripoll, José Posada-Villa, Charlene Rapsey, Nancy A Sampson, Juan Carlos Stagnaro, Dan J Stein, Margreet ten Have, Yolanda Torres, Cristian Vladescu, Peter W Woodruff, Zahari Zarkov, Ronald C Kessler, Sergio Aguilar-Gaxiola, Ali Al-Hamzawi, Jordi Alonso, Yasmin A. Altwaijri, Laura Helena Andrade, Lukoye Atwoli, Corina Benjet, Evelyn J. Bromet, Ronny Bruffaerts, Brendan Bunting, José Miguel Caldas-de-Almeida, Graça Cardoso, Stephanie Chardoul, Alfredo H. Cía, Louisa Degenhardt, Giovanni De Girolamo, Oye Gureje, Josep Maria Haro, Meredith G. Harris, Hristo Hinkov, Chi-yi Hu, Peter De Jonge, Aimee N. Karam, Elie G. Karam, Georges Karam, Alan E. Kazdin, Norito Kawakami, Ronald C. Kessler, Andrzej Kiejna, Viviane Kovess-Masfety, John J. McGrath, Maria Elena Medina-Mora, Jacek Moskalewicz, Fernando Navarro-Mateu, Daisuke Nishi, Marina Piazza, José Posada-Villa, Kate M. Scott, Juan Carlos Stagnaro, Dan J. Stein, Margreet Ten Have, Yolanda Torres, Maria Carmen Viana, Daniel V. Vigo, Cristian Vladescu, David R. Williams, Peter Woodruff, Bogdan Wojtyniak, Miguel Xavier, Alan M. Zaslavsky
Journal: The Lancet Psychiatry (2023)
Author correction to ‘Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA’ [Acta Pharmaceutica Sinica B 13 (2023) 2585–2600]
Authors: Wenxin Zhang, Xiaohui Pan, Yanjun Xu, Hongjie Guo, Mingming Zheng, Xi Chen, Honghai Wu, Fengming Luan, Qiaojun He, Ling Ding, Bo Yang
Journal: Acta Pharmaceutica Sinica B (2023)

[This corrects the article DOI: 10.1016/j.apsb.2023.04.002.].